Programmed cell death (PCD) is a physiological process required for the development of the nervous system. Deregulation of this process may contribute to the neuronal injury and cell death associated with neurodegenerative disorders. Recent data strongly suggest that overexpression of the cRel subunit of NF-kB, alone, is sufficient to protect sympathetic neurons from apoptosis caused by nerve-growth factor (NGF)-deprivation. Therefore, experiments are proposed to investigate the role of NFkB /Rel in mediating the survival of neurons. The present study will utilize sympathetic neurons as an in vitro model for PCD, based on their death after NGF withdrawal. The specific aims are designed to test the hypothesis that NF-kB regulates neuronal death in part by through its ability to compete with the pro-apoptotic factor c-Jun for binding to the co-activator protein p300/CBP, thereby inhibiting the activity of c-Jun. This hypothesis is based on recent evidence showing that NGF deprivation-induced apoptosis of sympathetic neurons requires c-Jun activity. Experiments are proposed to (1) define the specific subdomain(s) within cRel that is necessary for protection of sympathetic neurons from apoptosis due to NGF-withdrawal, (2) examine whether NF-kB can also protect primary neurons derived from the central nervous system (CNS) from a well-defined pro-apoptotic stimulus, and (3) investigate the effect of overexpression of the transcriptional co-activator p300 on NF-kB-mediated survival of neurons. It is expected that these studies will provide new insights into the pathogenesis of neurodegenerative diseases, and that they may ultimately contribute to the identification of pharmacological inhibitors of neuronal cell death.